2 - (4 - (3&#39;,5&#39; - diphenylcyclohexyl) - phenoxy)lower aliphatic monocarbocylic acids and esters thereof

ABSTRACT

THE INVENTION RELATES TO 2-(4-(3&#39;&#39;,5&#39;&#39;-DIPHENYLCYCLOHEXYL)PHENOXY) LOWER ALIPHATIC MONOCARBOCYLIC ACIDS AND THE CORRESPONDING LOWER ALKYL ESTERS, AND TO A PROCESS FOR THEIR PRODUCTION. THE COMPOUNDS ARE USEFUL AS HYPOLIPIDEMICS.

United "States Patent ()ffi-ce 3,598,852 Patented Aug. 10, 1971 US. Cl.260-473 3 Claims ABSTRACT OF THE DISCLOSURE The invention relates to2-[4-( 3',S'-diphenylcyclohexyl) phenoxy] lower aliphatic monocarbocylicacids and the corresponding lower alkyl esters, and to a process fortheir production. The compounds are useful as hypolipidemics.

wherein each of R and R independently represents hydrogen or straight Ichain lower alkyl preferably containing from 1 to 4 carbon atoms, i.e.,methyl, ethyl, propyl, and butyl; and

R represents hydrogen or straight or branched chain lower alkylpreferably containing from 1 to 4 carbon atoms, e.g., methyl, ethyl,propyl, isopropyl or butyl.

The compounds of Formula I are most conveniently prepared by reacting analkali-metal salt of 4-(3',5-diphenylcyclohexyl) phenol with anappropriate 2-halo substituted aliphatic acid or ester as illustrated bythe following reaction scheme:

wherein R R and R are as defined, X represents halogen having an atomicweight of from 35 to 127, i.e., chloro, bromo and iodo, and M representsan alkali-metal preferably sodium or potassium.

The above process is conveniently carried out in an inert organicsolvent and at elevated temperatures. Preferably the reaction is carriedout at a temperature of from about 20 C. to about C. and in the samesolvent employed for the preparation of the alkali-metal salt derivativeof Formula II from the corresponding phenol discussed in further detailhereinafter. The resulting product (I) is readily recovered inconventional manner.

It will be readily appreciated by one skilled in the art that thecompounds of Formula I wherein R is hydrogen, i.e., the free acids, mayalso be obtained from the corresponding esters of Formula I (i.e., WhereR is alkyl) by simple basic hydrolysis of the ester in conventionalmanner. The hydrolysis is conveniently carried out by treating the esterwith an alcoholic solution of an alkali-metal hydroxide, e.g., potassiumhydroxide in methanol.

Various of the 2-halo substituted alkanoic acids and esters of FormulaHI employed in the above-illustrated process are known and can beprepared by methods described in the literature. Such others which maynot be specifically described in the literature can be prepared fromavailable material in analogous manner.

The alkali-metal salts of 4-(3',5'-diphenylcyclohexyl) phenol (FormulaII) are conveniently prepared by reacting the corresponding phenol withan alkali-metal hydride, e.g., sodium hydride or potassium hydride, atroom temperature (2025 C.) in an inert substantially anhydrous organicsolvent. Suitable solvents include dimethylacetamide, diethylacetamideand dimethylformamide. As previously indicated hereinabove the solventemployed in preparing the phenolate is preferably employed in carryingout the subsequent reaction of the phenolate (H) with the appropriate2-halo substituted alkanoic acid or ester (III). The preparation of thephenol, i.e., 4-(3',5'-diphenylcyclohexyl)phenol is illustrated inExample 1 hereinafter.

The compounds of Formula I are useful because they possesspharmacological activity in animals. In particular, the compounds areuseful as hypolipidemic agents having hypocholestercmic and/orhypotriglyceridemic activity, as indicated by tests on a group of Whiterats which are given 10-50 mg. per kg. of body weight per diem of thecompound orally, for six days, followed by extraction with isopropanolof serum or plasma after anesthetizing the rats with sodiumhexobarbital, and then noting the cholesterol and triglyceride contentsas compared to those of a control group. The cholesterol andtriglyceride contents are determined by the methods described byLofland, H.B., Anal. Biochem. 9:393 (1964): (Technicon method N 24a):and Kessler, G., and Lederer, H. Technicon Symposium, Mediad Inc., NewYork, pages 345-347 (1965), respectively. For such usage, the compoundsmay be administered orally as such or admixed with conventionalpharmaceutical carriers. The dosage administered may vary depending onthe particular compound employed, the therapy desired and the severityof the condition being treated. In general, satisfactory re sults areobtained when administered at a daily dosage of from about 4 milligramsto about 30 milligrams per kilogram of animal body Weight, preferablygiven in divided doses, 2 to 4 times a day, or in sustained releaseform. For most mammals the total daily dosage is from about 0.05 gram toabout .4 gram of the compound, and the dosage forms suitable forinternal use comprise from about 12.5 milligrams to about 200 milligramsof active compound in intimate admixture with a solid or liquidpharmaceutically acceptable carrier or diluent.

For above usages, oral administration with carriers may take place insuch conventional forms as tablets, dispersible powders, granules,capsules, syrups and elixirs. Such compositions may be preparedaccording to any method known in the art for the manufacture ofpharmaceutical compositions, and such compositions may contain one ormore conventional adjuvants, such as sweetening agents, flavoringagents, coloring agents, and preserving agents, in order to provide anelegant and palatable preparation. Tablets may contain the activeingredient in admixture with conventional pharmaceutical excipients,e.g., inert diluents such as calcium carbonate, sodium carbonate,lactose and talc, granulating and disintegrating agents, e.g., starchand alginic acid, binding agents, e.g., starch, gelatin and acacia, andlubricating agents, e.g., magnesium stearate, stearic acid and talc. Thetablets may be uncoated or coated by known techniques to delaydisintegration and adsorption in the gastro-intestinal tract and therebyprovide a sustained action over a longer period. Similarly, suspensions,syrups and elixirs may contain the active ingredient in admixture withany of the conventional excipients utilized for the preparation of suchcompositions, e.g., suspending agents (methylcellulose, tragacanth andsodium alginate), wetting agents (lecithin, polyoxyethylene stearate andpolyoxyethylene sorbitan monooleate) and preservatives(ethyl-p-hydroxy-benzoate). Capsules may contain the active ingredientalone or admixed with an inert solid diluent, e.g., calcium carbonate,calcium phosphate and kaolin. The preferred pharmaceutical compositionsfrom the standpoint of preparation and ease of administration are solidcompositions, particularly hardfilled capsules and tablets.

The compounds of Formula I wherein R is hydrogen (i.e. free acids) maybe similarly administered in the form of their non-toxicpharmaceutically acceptable salts. Such salts do not materially differfrom the free acid forms in their pharmacological elfect and areincluded within the scope of the invention. As illustrative of suchsalts there may be included aluminum salt; non-toxic alkali metal salts,e.g., potassium and sodium salts; nontoxic alkaline earth metal salts,e.g., magnesium and calcium salts; salts with N-containing bases such asammonium salts and pharmaceutically acceptable primary, secondary andtertiary amine salts, e.g., ethanol amine salts, diethanol amine salts,and the like. Such salts are prepared in conventional manner.

A representative formulation is a tablet prepared by conventionaltabletting techniques and containing the following ingredients:

Ingredient: Weight (mg.)

2 methyl 2 [4-(3,5'-diphenylcyclohexyl) The following examples showrepresentative com pounds encompassed within the scope of this inventionand the manner in which such compounds are prepared. However, it is tobe understood that the examples are for purposes of illustration onlyand are not intended as in any Way limiting the scope of the inventionwhich is defined in the appended claims.

EXAMPLE 1 2-methyl-2-[4-(3,5'-diphenylcyclohexyl)phenoxy] propionic acidStep A: Preparation of 4-(p-methoxyphenyl)-2-oxo-6-phenyl-3-cyclohexene-l-carboxylic acid ethyl ester.To a solution of 93g. of 4-methoxychalcone (a known compound) prepared by reaction ofp-methoxyacetophenone and benzaldehyde dissolved in 6.5 liters absoluteethanol containing 54 g. anhydrous potassium carbonate is added 63.5 g.ethyl acetoacetate. The resulting mixture is stirred at room temperature(20 C.) for 22 hours, evaporated in vacuo to a thick slurry which istreated with 500 ml. methylene chloride. The resulting solution isfiltered and the filtrate evaporated in vacuo to obtain a viscous oilwhich is taken up in 350 ml. 95% ethanol. The crude product iscrystallized from the ethanol and recrystallization from ethanol gives4-(p-methoxyphenyl)-2-oxo- 6-phenyl-3 cyclohexene-l-carboxylic acidethyl ester, M.P. l05.5-l07 C.

Step B: Preparation of3-(p-methoxyphenyl)-5-phenyl-2-cyclohexen-1-one.To a solution of 43 g.of 4-(pmethoxyphenyl) 2 oxo-6-phenyl-3-cyclohexene-l-carboxylic acidethyl ester dissolved in 860 ml. acetic acid is added 430 ml.hydrochloric acid. The resulting mixture is refluxed overnight,evaporated in vacuo to obtain a crude oil which is dissolved in 500 ml.methylene chloride. The resulting solution is washed first with 200 ml.Water, then 200 m1. saturated sodium bicarbonate solution, and againwith 200 ml. water. The organic phase is dried over anhydrous magnesiumsulfate, evaporated in vacuo to remove solvent, and the resulting solidtwice crystallized from 350 ml. ethanol to obtain yellow needles of 3 (pmethoxyphenyD-S-phenyl-2-cyclohexen-l-one, M.P. 103-l04 C.

Step C: Preparation of 3-(p-hydroxyphenyl)-5-phenyl-2-cyclohexenl-one.To a solution of 2.8 g. of3-(pmethoxyphenyl)-5-phenyl-2-cyclohexen-l-one, dissolved under refluxin 50 ml. xylene is added a total of 2.32 .g. of aluminum chloride inthree separate additions. The resulting mixture is refluxed for 5 hours,cooled to 0 C., and poured onto ml. crushed ice. The organic phase isseparated, and dried over anhydrous magnesium sul fate. Crystallizationoccurs on evaporation in vacuo of the organic phase and the solidobtained is recrystallized from 95% ethanol to obtain 3-(p-hydroxyphenyl)-5-phenyl-2-cyclohexen-l-one, M.P. 2015-203 C.

Step D: Preparation of3-(p-hydroxyphenyl)-l,5-diphenyl-2-cyclohexen-1-ol.A solution of 26.4 g.of 37 (p hydroxyphenyl)-5-phenyl-2-cyclohexen-1-one in 100 ml. oftetrahydrofuran is added, over a period of 1 hour at --5 to 0 C., to anexcess of phenylmagnesium bromide (prepared by reacting 78.5 g. ofbromobenzene with 12.5 g. of magnesium turnings in 1.5 liters oftetrahydroq furan). The reaction mixture is then stirred at roomtemperature for 24 hours and then cooled to --l0 C. and treated with 300ml. of a saturated aqueous ammonium chloride solution. Thetetrahydrofuran is then evaporated in vacuo at a bath temperature of 30to 40 C. and to the residue is added 1 liter of diethyl ether. Thelayers are separated and the organic phase extracted twice with 200 ml.(each) of 1 N sodium hydroxide. The extracts are combined and acidifiedwith 60 ml. of concentrated hydrochloric acid. The acidified extract isthen extracted twice with 200 ml. (each) of diethyl ether and thecombined ether extracts washed first with 100 ml. of water, then with100 ml. of a saturated aqueous sodium bicarbonate solution and thendried over anhydrous magnesium sulfate and evaporated to obtain3(p-hydroxyphenyl)- 1,S-diphenyl-Z-cyclohexen-l-ol, M.P. 98 C. (aftercrystallization from hexane).

Step E: Preparation of 3,5-diphenyl-1-(p-hydroxyphenyl)cyclohexane.To asolution of 3-(p-hydroxyphenyl)- 1,S-diphenyl-Z-cyclohexen-1-ol(obtained from Step D) in 75 ml. of glacial acetic acid is added 2.0 g.of a 5% palladium on charcoal catalyst and the mixture hydrogenated at atemperature of 60 C. under 1500 p.s.i. hydrog en pressure. After thestoichiometric amount of hydrogen has been consumed (approximately 12hours) the mixture is filtered and the solvent evaporated in vacuo. Theresidue is dissolved in ethyl acetate and the resulting solution Washedtwice first with 50 ml. (each) of a saturated aqueous sodium bicarbonatesolution and then twice with 100 ml. (each) of water and then dried overanhydrous magnesium sulfate and evaporated to obtain 3,5 -diphenyl-1(p-hydroxyphenyl) cyclohexane.

Step F: Preparation of2-methyl-2-[4-(3',5-diphenylcyclohexyl)phenoxy]pr0pionic acid ethylester.To 4.8

- g. of sodium hydride (50% suspension in mineral oil) suspended in 200ml. of dry dimethylacetamide is added portionwise with stirring and atroom temperature 31.9 g. of 3,5-diphenyl-1-(p-hydroxyphenyl)cyclohexane.To the resulting mixture is added 20 g. of ethyl bromoisobutyrate andthe mixture heated at 100 C. on a water bath for 24 hours. The solventis then evaporated in vacuo and the residue taken up in 200 ml. ofdiethyl ether. The ether solution is then washed first with 200 ml. ofwater, then with 200 ml. of a saturated aqueous sodium bicarbonatesolution and then dried over anhydrous magnesium sulfate. The ether isthen evaporated off to obtain 2-methyl-2-[4-(3,5'-diphenylcyclohexyl)phenoxy1propionic acid ethyl ester.

Step G: Preparation of2-methyl-2-[4-(3',5'-diphenylcyclohexyl)-phenoxy]propionic acid.Amixture of 9 g. of 2-methyl-2-[4-(3,5' diphenylcyclohexyl)-phenoxy]propionic acid ethyl ester, 2.0 g. of potassium hydroxide and 40 ml. ofmethanol is allowed to stand at room temperature for 3 days. The solventis then evaporated in vacuo and the residue dissolved in Water. Theresulting solution is extracted twice with 50 ml. (each) of diethylether, and the combined ether extracts then acidified with 20 ml. of 2 Nhydrochloric acid and extracted three times with ml. (each) of asaturated aqueous sodium chloride solution. The organic phase is thendried over anhydrous magnesium sulfate and the solvent evaporated toobtain 2-methyl-2-[4-(3',5-diphenylcyclohexyl)phen0xy]propionic acid.

What is claimed is:

1. A compound of formula I O(|3COOR3 wherein each of JAMES A. PA'ITBN,Primary Examiner J. F. TERAPANE, Assistant Examiner US. Cl. X.R.

